Osteoporosis is under-reported in men and may be present in up to 31% of male VA patients. Further, it is among the most debilitating disorders for women - who make up an increasingly larger share of our Veteran population. Hip and vertebral fractures, major risks with osteoporosis, lead to loss of independence, pain, even potentially serious cardiac and brain morbidities, as well as increased mortality. Our main hypothesis is that the cytokine stromal-derived factor 1 (SDF-1, aka CXCL12) is increased in the peripheral circulation with age and contributes to age-associated bone loss. In the peripheral blood SDF-1 is rapidly converted to an N-terminal endopeptidase-cleaved form by the circulating dipetidlylpeptidase CD26 (dipetidlylpeptidase 4, DPP4). The cleaved form of SDF-1 binds to and blocks the SDF-1 receptor CXCR4, but does not activate it. It becomes in effect an inhibitor. Because of the quick alteration of SDF-1 by DPP4, but its slower total breakdown and removal, our research suggests the majority of the SDF-1 in the blood and bone marrow is of the inactive/inhibitory form. Part of our hypothesis is that if the level of the inactive form rises slowly, and stays up wth aging, then CXCR4 signaling is reduced long-term and this will have a negative impact on bone, reducing the number of BMSCs and reducing bone formation. There is increasing evidence that CXCR4 signaling is needed for BM mesenchymal stem cells (BMSCs) to maintain a progenitor cell population and to initiate and support osteogenesis. Importantly, preclinical murine studies from our laboratory have shown that circulating levels of total SDF-1, including the DPP4-cleaved form, increase with age in mice and that experimentally increasing the plasma level of DPP4-cleaved SDF-1 in young mice reduces bone formation serum markers and significantly decreases trabecular bone volume and bone density. This led to a funded NIH PO1 grant to determine the role of SDF-1 isoforms in the regulation of murine bone formation with age. The research studies proposed here are to see if our hypotheses and observations in mice are true in humans: We propose to test the novel hypothesis that in humans increased DPP4-cleaved SDF-1 isoforms are important factors in age-and disease-associated bone loss. We propose to assess the levels of circulating, and bone marrow, SDF-1 (DPP4-cleaved and non-cleaved) levels, DPP4 activity, and the effects of these isoforms on human BMSC's osteogenic activity in vitro and bone formation and quality/density in vivo. We will measure SDF-1 isoforms along with DPP4 in the serum and bone marrow of patients of different ages, and correlate this with their bone density and volume, as well as serum markers of bone formation or breakdown. We will also determine if there are changes in these SDF-1 and DPP4 parameters in patients with osteoporosis relative to age-matched controls. We further propose to determine the effects on bone formation of FDA-approved drugs in use for diabetic therapy, which act by regulating DPP4 activity (e.g. sitaglitin). We will determine if diabetic patients receiving treatment with these DPP4 inhibitors show improved bone formation compared to controls. Finally, we will use isolated human patient BMSCs to determine if DPP4 cleaved SDF-1 reduces BMSC cell survival, proliferation, and osteogenic potential. Additionally, these human BMSCs will be assessed to determine if there are age-associated changes in miRNAs targeting the SDF-1 axis and osteogenic genes. We will determine experimentally if such miRNAs affect BMSC cell fate. This work could rapidly lead to clinical trials of already FDA approved DPP4 inhibitors as a novel pro-bone remodeling treatment for osteoporosis as a replacement, or enhancement, of current problematic anti-remodeling therapies. In follow up studies, acute inhibition of DPP4 may also have value in increasing bone repair rates via increasing the active form of SDF-1 to increase stem cell homing and osteogenic induction following fracture, or other traumatic injury to bone, a critical need for the VA and DoD. Longer-term this work opens the potential to use regulation of specific miRNAs to regulate the osteogenic environment for BMSCs with age and to prevent osteoporosis.